Amyotrophic Lateral Sclerosis and Novel Therapeutic Strategies

Abstract

Research and key discoveries in the field of amyotrophic lateral sclerosis (ALS) have exponentially increased since the announcement in 1993 of the first ALS-causing mutations in the gene for the well-studied antioxidant enzyme Cu,Zn superoxide dismutase (SOD1). The etiology of sporadic ALS largely remains unknown and the mechanisms of motor neuron degeneration are still being investigated. The only FDA drug approved for the treatment of ALS is riluzole with only modest benefit to patients, but multiple drugs are currently in the development pipeline and in human ALS clinical trials. In this special issue, K. Venkova-Hristova et al. thoroughly reviewed studies of experimental therapeutics in animal models of ALS, including specific examples of those that proceeded into human clinical trials. Since none of the ALS human clinical trials succeeded despite positive results in animal models, the question of “why” has been on everyone's mind, with efforts to develop superior alternatives. This review discusses the potential reasons for the universal failure of preclinical successes to translate into positive clinical outcomes. It has become obvious that the lack of understanding of the precise mechanisms of motor neuron degeneration presents a major obstacle in the development of effective therapy for ALS. This review discusses the details of several major pathogenic pathways in ALS and the efforts of various groups to block one toxic pathway at a time, ranging from oxidative stress to protein aggregation. The authors discuss the pros and cons of ALS models and propose simultaneous targeting of multiple pathways as a more efficient strategy, due to the multifactorial nature of ALS pathology.